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Sickle cell anemia is the most common form of sickle cell disease and is due to homozygosity of the substitution of valine for glutamate at the β6 position, giving rise to mutant βS-globin forming sickle hemoglobin (HbS, α2βS2). Other forms of sickle cell disease include hemoglobin SC disease where both HbS and HbC (caused by a glutamate to lysine substitution at the β6 position giving rise to mutant βC-globin) coexist and HbS-β thalassemia (combination of 1 mutant βS-globin gene and mutation in the other β-globin gene resulting in reduced or no normal β-globin production). In all these cases, the dysfunction of HbS is the primary cause of the disease. Almost all of the major physiologic properties of HbS in dilute solution (eg, oxygen, carbon dioxide, 2,3-diphosphoglyceric acid [DPG], and hydrogen ion binding, as well as the cooperativity of oxygen binding) are normal. However, the low solubility upon deoxygenation of HbS, as compared to the very high solubility of the deoxy form of HbA (α2β2), at the high concentrations inside the red cell, causes aggregation of the hemoglobin molecules, which is the major direct effect of the sickle mutations (βSGlu6→Val). We assume that abnormal red cell flow properties in the circulation and the accompanying increase in hemolysis and thus all clinical manifestations can be traced back to this phenomenon. The major factors affecting the effective solubility inside the red cell are the intracellular hemoglobin composition and concentration and the oxygen saturation, whereas other cellular variables have smaller effects (see Figure 2-1 for overview of this paradigm).


Overview of chapter. The mutant HbS molecules, with a valine residue at position 6 of the beta chains due to the GTG substitution for GAG in the sixth codon of the DNA, are soluble (however, in very concentrated solution) within the sickle erythrocyte in the oxygenated form (small red circles). Upon partial deoxygenation of the red cells, as in the normal transit through the human circulation, the deoxygenated (deoxy) HbS molecules in the cells (now shown as small blue circles in the middle of the diagram) begin to aggregate into strands that then grow and self-associate to form higher-order fibers. For illustrative purposes only, the deoxy molecules, as at total deoxygenation, are shown in this diagram.

These polymer fibers, as they accumulate and align further, decrease the flexibility of the sickle erythrocytes needed to transit the microcirculation but eventually will distort the shapes of these cells (shown as partially deoxygenated red cells at the bottom of the diagram), increase fragility-promoting hemolysis, and cause membrane damage. Although many factors determine the amount and detailed structure of the HbS polymer in the cells, at any oxygen saturation, the intracellular hemoglobin concentration and composition and 2,3-diphosphoglyceric acid (DPG) levels are probably the most important variables. This chapter is designed to summarize knowledge of the formation of intracellular HbS ...

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